ATF4在稳态和肥胖状态下驱动调节性T细胞的功能特化。

ATF4 drives regulatory T cell functional specification in homeostasis and obesity.

作者信息

Wang Ke, Farrell Andrea, Zhou Enchen, Qin Houji, Zeng Zixuan, Zhou Kailun, Cunha E Rocha Karina, Zhang Dinghong, Wang Gaowei, Atakilit Amha, Sheppard Dean, Lu Li-Fan, Jin Chunyu, Ying Wei

机构信息

Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA, USA.

School of Biological Sciences, University of California, San Diego, La Jolla, CA, USA.

出版信息

Sci Immunol. 2025 Mar 14;10(105):eadp7193. doi: 10.1126/sciimmunol.adp7193.

DOI:10.1126/sciimmunol.adp7193

PMID:40085690

Abstract

Regulatory T cells (T) have diverse functional specification in homeostasis and disease. However, how liver T function and are transcriptionally regulated in obesity is not well understood. Here, we identified that effector T expressing activating transcription factor 4 (ATF4) were enriched in the livers of obese mice. ATF4 was critical for driving an effector T transcriptional program, and ATF4-expressing T promoted the development of obesity-induced liver fibrosis by enhancing transforming growth factor-β activation via integrin αvβ8. T-specific deletion of resulted in reduced liver T and attenuation of obesity-induced liver abnormalities. Furthermore, ATF4 was required to promote the differentiation of nonlymphoid tissue T precursors under steady state. These findings demonstrate that ATF4 is important for regulating T functional specification in homeostasis and obesity.

摘要

调节性T细胞（T细胞）在体内稳态和疾病中具有多种功能特性。然而，肥胖状态下肝脏T细胞的功能及其转录调控机制尚不清楚。在此，我们发现表达激活转录因子4（ATF4）的效应T细胞在肥胖小鼠肝脏中富集。ATF4对于驱动效应T细胞转录程序至关重要，表达ATF4的T细胞通过整合素αvβ8增强转化生长因子-β的激活，从而促进肥胖诱导的肝纤维化发展。T细胞特异性缺失导致肝脏T细胞减少以及肥胖诱导的肝脏异常减轻。此外，在稳态下，ATF4是促进非淋巴组织T细胞前体分化所必需的。这些发现表明，ATF4对于在体内稳态和肥胖状态下调节T细胞功能特性很重要。